Project Summary/Abstract: Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Potential interventions are needed due to the current lack of effective preventative or therapeutic treatments. The nicotinic acetylcholine receptor (nAChR) agonist, nicotine, is capable of preventing the development of mechanical allodynia induced by paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, in a mouse model of CIPN. Previous studies suggest that CIPN, specifically induced by paclitaxel, may be a result of inflammatory processes. The literature also demonstrates that nicotine can protect neurons from various sources of toxicity via activation of the ?7 nAChR subtype. Therefore, the aims of this work are to determine if nicotine is neuroprotective in a mouse model of paclitaxel-induced peripheral neuropathy via the ?7 nAChR. Wild-type and ?7 nAChR knockout mice will be treated with paclitaxel and/or nicotine followed by an assessment of mechanical allodynia with the von Frey test and of intra-epidermal nerve fiber (IENF) loss with confocal microscopy. Subsequently, the site of nicotine-mediated ?7 nAChR activation will be investigated with Cre/lox macrophage-specific knockout of the ?7 nAChR. These mice will also be treated with paclitaxel and/or nicotine, then tested for mechanical allodynia and analyzed for pro-inflammatory cytokines via an ELISA in various sensory tissues, including the hind paw epidermis, dorsal root ganglia, and spinal cord. After identifying the involvement of the ?7 nAChR in the protective role of nicotine, the pro-inflammatory effects of paclitaxel and potential anti-inflammatory role of nicotine will be further investigated by evaluating macrophage infiltration/microglial activation via immunohistochemistry. Lastly, nicotine will be chronically administered alone and in combination with paclitaxel in non-small cell lung cancer tumor-bearing mice in order to ensure that nicotine will not stimulate tumor growth or interfere with the anti-tumor effects of paclitaxel in vivo. Findings of the proposed work can be utilized to develop selective agonists and allosteric modulators for the ?7 nAChR to further improve efficacy and minimize any potential side effects or remaining concerns regarding nicotine. Most importantly, it is possible that this site of therapeutic intervention is common to some or all neuropathy-inducing chemotherapy drug classes, including vincristine, platinum compounds, and bortezomib.